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Oncogenic KRAS drives lipo-fibrogenesis to promote angiogenesis and colon cancer progression

ABSTRACT: Oncogenic KRAS (KRAS*) contributes to many cancer hallmarks. In colorectal cancer (CRC), KRAS* has been shown to suppress anti-tumor immunity which promotes tumor metastasis. Here, we show that the protumor actions of KRAS* extend to the adipogenic transformation of fibroblasts into lipid-laden cancer-associated fibroblasts (CAFs), which spur angiogenesis. Mechanistically, KRAS*-mediated activation of the transcription factor CP2 (TFCP2) resulted in TFCP2-mediated transcriptional upregulation of pro-adipogenic factors BMP4 and WNT5B to drive lipid-rich CAF transformation. Functionally, these lipid-rich CAFs promoted tumor growth via their production of vascular endothelial growth factor A (VEGFA). Correspondingly, genetic and pharmacological neutralization of TFCP2 decreased the abundance of lipid-rich CAFs, reduced tumor angiogenesis, and increased survival in an autochthonous KRAS*–driven CRC mouse model. These murine findings mirror translational profiles in human CRC. Thus, KRAS* transforms the stromal cell state to promote tumor angiogenesis and disease progression, providing an actionable therapeutic intervention for KRAS*–driven CRC.

ORGANISM(S): Mus musculus

PROVIDER: GSE229559 | GEO | 2023/09/15

REPOSITORIES: GEO

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2020-05-26 | PXD014019 | Pride

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2022-03-03 | PXD029507 | Pride

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Project description:KRAS mutation is one of the major genetic alterations in colorectal cancer (CRC). Treating patients with KRAS mutant CRC remains one of the biggest challenges in oncology. In this study, we aimed to discover an effective therapeutic microRNA (miRNA) that could target KRAS mutant CRC. For this purpose, we investigated the functional relevance of dysregulated miRNAs in KRAS mutant cancers. We transfected exogenous KRASG12V into human embryonic kidney 293 (HEK293) cells and human lung fibroblasts (MRC5) cells, and performed comprehensive microRNA expression profiling by microarray analysis. The results showed that 6 miRNAs are significantly upregulated in KRAS-transfected HEK293 and MRC5 cells. Among 6 miRNAs, we identified mature miRNA-29b-1-5p as potent growth inhibitor in CRC cell proliferation. However, miRNA-29b-1-5p was found to be a passenger strand with a star form (miRNA-29b-1-5p*), and did not function in CRC cells. Proliferation assay revealed that completely opposite complementary strand to miRNA-29b-1-5p possessed a potent anti-tumor effect. We named this novel anti-tumor siRNA sequence “MIRTX”. MIRTX induced apoptosis and significantly inhibited cell proliferation in KRAS mutant CRC in vitro. In addition, MIRTX suppressed NF-κB signaling pathway, which is downstream effector of KRAS in CRC. Furthermore, MIRTX directly targeted 3'-UTR of PIK3R1 and CXCR2 mRNA, and indirectly suppressed KRAS itself. In vivo xenograft mouse models, systemic administration of MIRTX significantly inhibited the tumor growth with no particular toxicity, using carbonate apatite as a vehicle. These findings indicate that inhibition of NF-κB signaling by siRNA-based therapeutic could be a promising strategy against KRAS mutant CRC.

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2009-09-13 | E-GEOD-17817 | biostudies-arrayexpress

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